Familial Hypercholesterolemia

Familial Hypercholesterolemia

National Organization for Rare Disorders, Inc.


It is possible that the main title of the report Familial Hypercholesterolemia is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • autosomal dominant hypercholesterolemia

Disorder Subdivisions

  • LDL receptor disorder
  • familial ligand-defective apolipoprotein B
  • PCSK9
  • heterozygous familial hypercholesterolemia
  • homozygous familial hypercholesterolemia

General Discussion


Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. The current National Cholesterol Education Program Adult Treatment Panel III defines major CHD risk factors as cigarette smoking, high blood pressure, age (men 45 or older; women 55 or older), family history of premature CHD in parents or siblings (men before age 55; women before age 65) and HDL cholesterol below 40 mg/dL. Patients with diabetes are currently considered to have a risk for a heart attack (fatal or nonfatal) as great as those who have already had a heart attack.


In 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the mutations in the gene that interfered with its function. A normally functioning receptor lowers the blood levels of LDL cholesterol by taking up the particles (lipoproteins) that carry the bad cholesterol. A mutation in one of the genes caused a decrease either in the number or function of the receptors, resulting in the extreme LDL cholesterol elevations of FH. Goldstein and Brown became the first investigators to identify a mutation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Since that time, other genes have been identified that cause severe hypercholesterolemia.

Almost all genes have two copies, one inherited from each parent's chromosome. A dominant mutation is expressed if only one copy is present. A recessive mutation must be present in both chromosomes. FH patients who carry a single mutation have heterozygous FH and those with a mutation on both chromosomes have homozygous FH.



Heterozygous FH:

Vascular Conditions

- CHD (arteries supplying the heart) may cause angina (chest pain), nonfatal or fatal heart attacks, need for angioplasty (opening up a coronary artery causing angina or risk of a heart attack), or sudden death.

- Cerebrovascular disease (arteries supplying the brain) may cause stroke or transient ischemic attack (TIA), symptoms of a stroke that last only a brief time and which do not permanently injure the brain.

- Peripheral vascular disease (arteries supplying the limbs, predominantly the legs) may cause pain when walking that is relieved by rest (claudication) and at its most severe, pain at rest that can result in amputation of the affect area (toe, leg).

- Aortic aneurysm (weakening causing bulge in the wall of the major artery supplying all other arteries) that may rupture (burst), causing catastrophic bleeding and often death.

Conditions Other Than Vascular

- Elevated total and LDL cholesterol levels (see below)

- Xanthomas: Approximately 60% of affected individuals develop firm nodules under the skin caused by deposition of cholesterol on tendons. The most common sites are the Achilles tendon and tendons on top of the hands. Achilles tendon xanthomas may cause tendonitis, an inflammation of the tendon that may tear or rupture.

- Corneal arcus: an opaque, white line within the margin of the cornea that is above or surrounds the cornea. It may be present in people with normal cholesterol levels, particularly as they age and is found more frequently in African Americans whose cholesterol levels are normal.

- Xanthelasmas: cholesterol deposits on, above or under the eyelids. They may be present in people with normal cholesterol levels, particularly as they age.

Homozygous FH:

Individuals with homozygous FH usually have xanthomas by early childhood. Planar xanthomas affecting the skin on the hands, elbows, buttocks and knees in a young child are diagnostic for this condition. Corneal arcus surrounding the entire inside edge of the cornea is often present. Because the mutation is dominant, both parents are "obligate" heterozygotes and will have high LDL cholesterol levels and a high likelihood of premature CHD. Rarely one of the mutations arises from a spontaneously occurring mutation, in which case one of the parent's would have an average cholesterol level. Young children may die of a major coronary event if not aggressively treated. Aortic stenosis (narrowing of the heart valve leading to the aorta) often occurs.



Heterozygous FH occurs when a child inherits the abnormal gene from a parent who has heterozygous FH. The risk of passing the abnormal gene from one affected parent to offspring is 50% for each pregnancy regardless of the sex of the child. An abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual.

In homozygous FH, both parents have heterozygous FH. The risk of having a child with homozygous FH is 25% and the risk of having a child with heterozygous FH is 50%. The remaining 25% will inherit a normal gene from each parent.

If one parent has homozygous FH and the other does not, the risk that their children will have heterozygous FH is 50%; none will have homozygous FH unless the normal parent's gene for the LDL receptor acquires a mutation.

Genetic Subdivisions of Familial Hypercholesterolemia

An LDL receptor mutations is the cause of approximately 90% of cases of heterozygous FH. Since the original mutation discovered by Goldstein and Brown, over 1600 other mutations of the same gene have been identified.

Familial defective apolipoprotein B-100 is responsible for approximately 10% of FH cases. It is caused by a mutation in the gene coding for the protein apolipoprotein B-100, which is a ligand that enables uptake of lipoproteins by the liver. A ligand is analogous to the key for a lock, which in this case is the LDL receptor. The mutation is more often found in those of Northern European descent.

PCSK9 (proprotein convertase subtilisin/kexin type 9) PCSK9 is responsible for only a small percentage of FH cases. The mutation in this gene is unlike most mutations, which cause dysfunction of the affected gene. The PCSK9 mutation increases the gene's function (a "gain-of-function" mutation). Its action causes a decrease in the number of LDL receptors and thereby increases the LDL cholesterol level.

Affected Populations

Affected Populations

In the United States and most other countries, 1 in 300 to 500 people has heterozygous FH. Small subpopulations around the world have a higher incidence, e.g. Afrikaners, French Canadians, some locales in the Middle East. The frequency of homozygous FH is 1 in 1 million.

Standard Therapies

Standard Therapies


At least 3 methods have been developed that use clinical data to confirm the diagnosis of heterozygous FH. Each uses slightly different criteria that include several of the following components:

- Elevated total cholesterol levels (e.g. greater than 300 mg/dL in adults and 260 in children)

- Elevated LDL cholesterol level (e.g. greater than 190 mg/dL in adults and 160 in children)

- Tendon xanthomas

- Family history for definite FH

- Family history of premature CHD

- Genetic analysis

One investigator (Peter P. Toth) recently suggested that the following LDL cholesterol levels strongly suggest FH and should prompt further investigation to confirm the diagnosis:

o 250 mg/dL or higher in patients age 30 or older

o 220 mg/dL or higher in patients age 20-29

o 190 mg/dL or higher in patients under age 20

A diagnosis of FH should prompt screening of patients' close relatives. Cascade screening has been recommended as a cost-effective strategy for genetic testing. After a patient (the index patient) has been identified by the established clinical criteria, the diagnosis is confirmed by DNA analysis. If a mutation is identified, the patient's first degree relatives (parent, sibling, child) are screened using clinical criteria. A new case is treated as an index case with genetic testing that, if positive, is followed by screening of first degree relatives. Cascade screening has been shown to be effective in finding patients with definite FH who were not being treated.

It should be understood that confirming the diagnosis of FH does not substantially affect treatment of elevated LDL cholesterol levels, though in some cases it could lead to slightly more aggressive management. The current National Cholesterol Education Program guidelines state that the goal LDL cholesterol level for patients with atherosclerotic disease or diabetes should be less than 100 mg/dL or less than 70 mg/dL for those at particularly high risk. For patients without these conditions, the goal LDL cholesterol depends on the presence of major CHD risk factors and, in most cases, is less than 130 mg/dL or, for those at lowest risk, less than 160 mg/dL. However, a diagnosis of FH could impact on these goals by taking into account that FH suggests a risk for CHD greater than that conferred by the same cholesterol level in a patient without FH. Therefore a firm diagnosis of FH could prompt more aggressive treatment than would otherwise be undertaken.

Homozygous FH is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL cholesterol levels, in the range of 800-1000 mg/dL. Both parents will have LDL cholesterol levels consistent with heterozygous FH and may have early CHD.


Treatment of FH is focused on reducing the LDL cholesterol levels and thereby decreasing the risk for atherosclerotic heart disease.

Heterozygous FH:

Lifestyle intervention

Dietary changes have the greatest LDL cholesterol-lowering impact, most importantly severely restricting saturated fat and eliminating trans fats. Decreasing dietary cholesterol and increasing fiber are also helpful. Diet composition should be primarily vegetables, whole fruit and grains, nuts and legumes. Seafood, lean poultry and low fat dairy products are the preferred sources of animal protein.

Weight loss and aerobic exercise have modest effects but have the added benefit of lowering blood pressure, blood sugar levels and cardiovascular risk.

Cholesterol lowering medication

- Statins:

Statins are, in most cases, the drug of choice to lower LDL cholesterol levels. They have been proven to reduce major cardiovascular events (heart attacks, stroke) and total mortality. Patients with heterozygous FH should be treated with one of the stronger statins: atorvastatin (Lipitor), pitavastatin (Livalo) or rosuvastatin (Crestor). Atorvastatin and rosuvastatin are approved for use in children by the Federal Drug Administration, as have all of the weaker statins.

Muscle injury is the major risk of statins but is rare, approximately 1/10,000. Liver damage is either nonexistent or minor.

A second agent to lower the LDL cholesterol is usually necessary by middle age if not before. Choices include:

- Niacin (Niaspan, Slo-Niacin)

- Ezetimibe (Zetia) is approved for use in children by the Federal Drug Administration

- Bile acid sequestrants:

Colesevelam (Welchol) is the most easily tolerated drug in this class but can cause constipation and interfere with the absorption of some other medications. It is approved for use in children by the Federal Drug Administration

In some cases, 3 drugs are required to lower the LDL cholesterol sufficiently. In patients who cannot achieve the desired LDL cholesterol level, a procedure called LDL apheresis may be necessary (see below).

Homozygous FH:

Survival of homozygous FH patients beyond young adulthood is unlikely without one of the following procedures both of which substantially lower LDL cholesterol levels.

- LDL apheresis:

Blood is withdrawn from a vein via a catheter and processed to remove LDL particles. Normal blood products are returned via another catheter. LDL cholesterol levels decrease approximately 50% but rise between apheresis sessions, which are necessary every 1-2 weeks. The procedure is expensive, time-consuming and not widely available.

- Liver transplantation:

As the donor liver will have normal LDL receptors, the LDL cholesterol quickly normalizes after the procedure but the risks of any organ transplant are substantial: complications from major surgery and lifelong suppression of the immune system. Patients with familial defective apoB have normal LDL receptors but the protein that binds to the receptor is abnormal.

Investigational Therapies

Mipomersen (ISIS 301012)

Isis Pharmaceuticals and Genzyme

Interferes with the production of apolipoprotein B-100

Being studied in patients with heterozygous and homozygous FH

Lomitapide (AEGR-733)

Aegerion Pharmaceuticals Inc.

Lowers LDL cholesterol and triglyceride levels

Being studied in homozygous FH patients and in patients with extremely high triglyceride levels.

PCSK9 inhibitors

Several companies are working on drugs that inhibit production of this protein. If effective, they will lower LDL cholesterol levels by preventing PCSK9 from decreasing LDL receptors.

Information on current clinical trials

All studies receiving U.S. government funding and some supported by private industry are posted on the Internet at www.clinicaltrials.gov

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll free: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources see:




Goldberg AC, Hopkins PN, Toth PP, et al. Executive Summary. Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients. J Clin Lipidology 2011;5:133-40.

Kwiterovich PO Jr. Clinical implications of the molecular basis of familial hypercholesterolemia and other inherited dyslipidemias. Circulation. 2011;123:1153-1155.

Lughetti l, Bruzzi P, Predieri B. Evaluation and management of hyperlipidemia in children and adolescents. Curr Opin Pediatr 2010;22:485-93.

McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, Daniels SR. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation 2007;115: 1948-1967.

Goldstein JL, Brown MS. The Cholesterol Quartet: 2001 Science 292 (5520): 1310-1312

Expert panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97


Centers for Disease Control and Prevention. http://www.cdc.gov/genomics/resources/video/RNed/index.htm. Updated October 18, 2010. Accessed September 20, 2011.

Citkowitz E. Familial hypercholesterolemia. eMedicine. Updated 2009. http://emedicine.medscape.com/article/121298-overview

Learn Your Lipids - Patient information from the Foundation of the National Lipid Association. http://www.learnyourlipids.com/

MEDPED (Make Early Diagnosis To Prevent Early Death)

Non-profit project to help treat individuals and families with FH

University of Utah

Salt Lake City UT 84108

Phone #: 801-581-3888

800 #: 888-244-2465

e-mail: s.larrinaga-shum@utah.edu


Medline Plus - U.S. National Library of Medicine, National Institutes of Health http://www.nlm.nih.gov/medlineplus/ency/article/000392.htm


American Heart Association

7272 Greenville Avenue

Dallas, TX 75231

Tel: (214)784-7212

Fax: (214)784-1307

Tel: (800)242-8721

Email: Review.personal.info@heart.org

Internet: http://www.heart.org

NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/

For a Complete Report

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